3-substituted chromones

ABSTRACT

3-SUBSTITUTED CHROMONES HAVING THE FOLLOWING STRUCTURAL FORMULAS ARE DISCLOSED.   3-(R1-CH2-),4-(O=),R2-4H-CHROMENE, OR ((4-(O=),R2-4H-   CHROMEN-3-YL)-CH2)2-R3   WHEREIN R1 IS HALOGEN, CYANO, CARBOXY, CARBOXAMIDE, AMINO, ALKYLAMINO, ARYLAMINO, ALKOXY, N-ALKYLHYDROXYLAMINO, ACYLOXY, AMIDO AND IMIDO; R2 IS HYDROGEN, HALOGEN, LOWER ALKOXY; AND R3 IS AMINO, ALKYLENDIAMINO SUCH AS ETHYLENEDIAMINO, ETC., CYCLIC DIAMINO SUCH AS PIPERAZINE-1,4-DIYL-HYDROXYLAMINO, -O- OR -S-. THEY ARE USEFUL IN PREVENTING ALLERGIC MANIFESTATIONS. COMPOUNDS OF THIS TYPE ARE PREPARED FROM 3-(HYDROXYMETHYL)CHROMONES.

United States Patent 3,767,679 3-SUBSTITUTED CHROMONES Maximillian vonStrandtmann, Rockaway, Sylvester Klutchko, Hackettstown, and JohnShave], Jr., Mendham, N.J., assignors to Warner-Lambert Company,

Morris Plains, NJ.

No Drawing. Filed Sept. 13, 1971, Ser. No. 180,073

Int. Cl. C07d 7/34 US. Cl. 260-3451 12 Claims ABSTRACT OF THE DISCLOSURE3-substituted chromones having the following structural formulas aredisclosed.

O O l l CH1 R1 CHz- R3 l 4 I II wherein R is halogen, cyano, carboxy,carboxamido, amino, alkylamino, arylamino, alkoxy, N-alkylhydroxylamino,acyloxy, amido and imido; R is hydrogen, halogen, lower alkoxy; and R isamino, alkylenediamino such as ethylenediamino, etc., cyclic diaminosuch as piperazine-l,4-diyl,hydroxylamino, -O or S--. They are useful inpreventing allergic manifestations.

Compounds of this type are prepared from 3-(hydroxymethyl)chromones.

The present invention relates to new and novel 3-substituted chromoneshaving the following structural forwherein R is halogen, cyano, carboxy,carboxamido, amino, alkylamino, arylamino, alkoxy, N-alkylhydroxylamino,acyloxy, amido or imido; R is hydrogen, halogen or lower alkoxy; and Ris amino, alkylenediamino, hydroxylamino, cyclic diamino, O- or S-.

In the above definitions for R R and R the term alkyl and the alkylportions in alkylamine and alkoxy are meant to contain from 1 to 7carbon atoms; the term acyl is meant to be the residue derived from icealkanoic acids of 1 to 7 carbon atoms and benzoic acid; the termalkylene in alkylenediamine is meant to contain from 2 to 7 carbon atomsand the term cyclic diamino is meant to include a 5- or 6-memberednitrogen containing heterocyclic rings such as piperidino, piperazinoand the like.

The compounds of this invention are useful in alleviating allergicmanifestations such as bronchial asthma. Thus, for example, when thesecompounds are tested in experimental animals such as rats in accordancewith the procedures of Mota, Life Sciences, 7, 465 (1963); Ovary et al.,Proc. Soc. Exptl. Biol. Med., 81, 584 (1952) they prevent allergicreactions at an intramuscular dose of S to 20 mg./ kg.

In order to use these compounds to provide, for example, symptomaticrelief of asthma a dose range of from 5 to 20 mg. per kilogram of bodyweight (1 to 3 times daily) is prescribed. This regimen can be varied bymethods well known to the healing arts depending upon the severity ofthe allergic condition and the species of the animal being treated butis within the above range.

To administer these compounds orally they are formulated, for example,with diluents such as lactose, dicalcium phosphate into tablets orencapsulated in gelatin capsules.

To administer these compounds parenterally they are formulated withdiluents such as peanut oil into an injecter suitable for intramuscularadministration.

The compounding of the above dosage forms are by known techniques fortableting and injection preparations by methods well known in thepharmacists art.

According to the present invention, these 3-substituted chromones areprepared in accordance with the following reaction scheme.

Referring now to the scheme, it will be seen that compound A is thestarting compound and it is treated in a variety of ways to give thecompounds of this invention.

Thus, A is treated with an acid anhydride, for example, with aceticanhydride under reflux conditions to give those compounds of theinvention where R is acyloxy.

To obtain compound H, compound A is treated to remove H O in an alcoholsolvent. Typically, for example, A is treated with iodine in a mixtureof methanol and acetone at room temperature. The resulting product isrecovered by conventional procedure.

Compound B is obtained by treating A with thionyl chloride. Compound Bis subsequently treated, for example, with potassium phthalimide toyield C. Compound C is then treated under acidic conditions to obtaincompound D where R is amino.

Compound B is further treated with a cyanide, e.g., potassium cyanide toyield the corresponding nitrile E which under acidic conditions yieldscompound F where R is carboxamido and carboxy.

Compound B is also reacted with different types of amines to give otherR substituted compounds of this invention. Among the various amineswhich may be used are, for example, l-methylpiperazine, piperazine,hydroxylamine, benzylamine, methylamine, amino pyridine, and the like.

Compound of type J is obtained by thermal dehydration at 260 C. ofcompound A.

The starting compound A is prepared in accordance with the procedure setforth in our copending application, Ser. No. 112,765, filed on Feb. 4,1971, now abandoned.

CI-hOCOR R2 i i R.

In order to further illustrate the practice of this invention thefollowing examples are given:

EXAMPLE 1 3- (chloromethyl chromone Thionyl chloride, 119 g. (1.0 mol),was added over 5 minutes to a stirred mixture of 100 g. (0.568 mol) of3- (hydroxymethyl)chromone and 800 ml. of benzene. Mild cooling wasnecessary to keep the temperature at 35 C. After minutes at C. thesolution was warmed to distill 011 most of the excess thionyl chlorideand benzene. Another 800 ml. of benzene was added and distilled to about500 ml. volume when crystals began to separate. The cooled mixture wasfiltered to give 65 g. of product melting at 108-112" C. Upon additionof 500 ml. of petroleum ether to the filtrate a second crop of 17.0 g.was obtained, M.P. 109-1l3 C. Total weight was 82 g. (74;%).

Recrystallization from ethyl acetate-petroleum ether gave pure materialmelting at 109-113 C.

Analysis for c,,H,c1o (percent): Calcd: C, 61.72; H, 3.63; Cl, 18.22.Found: C, 61.80; H, 3.57; Cl, 18.15.

EXAMPLE 2 3-chromonylacetonitrile A quantity of 15.0 g. (0.0764 mol) of3-(chloromethyl)-chromone was added to a stirred mixture of 29.25 g.(0.45 mol) of potassium cyanide and 150 ml. of metha- I101. The reactionwas mildly exothermic and the temperature was kept at 35 C. with mildcooling. After five minutes the mixture was diluted to one liter volumewith ice water. The separated orange, tacky solid was filtered,

washed well with water and dried. Weight 13.1 g. (92.7); MP. l25129 C.

Recrystallization from ethyl acetate gave pure material melting atl37-l39 C. in 66% yield.

Analysis for CnHqNOg (percent): Calcd.: C, 71.35; H, 3.81; N, 7.56.Found: C, 71.35; H, 3.81; N, 7.39.

EXAMPLE 3 3-chromonylacetic acid A mixture of 6.5 g. (0.035 mol) of3-chromonylacetonitrile and 40 ml. of concentrated hydrochloric acid washeated with stirring on the steam bath (using condenser). All soliddissolved and after 5 minutes crystals separated. The mixture was heatedfor an additional 15 minutes when ml. of water was added. The mixturewas cooled, filtered, Washed well with water and dried to give 6.0 g.(84%) of cream colored crystals melting at 218-221 C.

Recrystallization from 2-propan0l gave pure product melting at 220-222C.

Analysis for C H O (percent): Calcd: C, 64.71; H, 3.95; O, 31.34. Found:C, 64.89; H, 4.03; O, 30.98.

EXAMPLE 4 3-chromonylacetamide A quantity of 5.0 g. (0.027 mol) of3-chrornonylacetonitrile was added to 50 ml. of concentratedhydrochloric acid at room temperature with stirring. Most of the soliddissolved after one half hour. The reaction was filtered through asintered glass funnel to remove traces of undissolved and cold waterml.) was added to the filtrate. The separated solid was filtered, washedwell with water and dried. Weight 3.9 g. crude, Ml. 176"184 C.

Purification was effected by dissolving the crude in 300 ml. hotabsolute ethanol, filtering off undissolved solid, cooling in ice bath,filtering and drying. Weight 2.4 g. (43.8%), M.P. 201-205 C.

Further recrystallization from absolute ethanol gave pure materialmelting at 210-212 C.

Analysis for C H NO (percent): Calcd.: C, 65.02; H, 4.46; N, 6.89.Found: C, 65.00; H, 4.61; N, 7.00.

EXAMPLE 5 3-[ (4-methyll-piperazinyl)methyl] chromone A quantity of 10.0g. (0.051 mol) of 3-(chloromethyl)- chromone was added gradually to 70ml. of l-methylpiperazine. The reaction was mildly exothermic as somesolid separated. The stirred mixture was heated on the steam bath forone hour. Most of the excess base was removed on the rotary vacuumevaporator. Water (150 ml.) was added to the residue. Solid potassiumcarbonate was added to saturate and the separated oil was taken up into500 ml. of ether. The ether solution was dried (K COg), charcoaled,filtered and concentrated. Xylene (150 ml.) was added and stripped-0E atreduced pressure to chase the l-rnethylpiperazine. This process wasrepeated. The viscous base was dissolved in 100 ml. of 2-propanol andthe solution was treated with a moderate amount of hydrogen chloride.Ether (20 ml.) was added and crystals separated. Weight 8.5 g., M.P.199-201 C. On addition of additional ether to the filtrate 9.5 g. of acrop 2 was obtained, M.P. 228-233 C. Crop No. 1 was recrystallized fromabsolute ethanol-ether to give 6.0 g. crystals, M.P. 204-206 C. A testrecrystallization did not raise the melting point. An elemental analysisshowed this material to be slightly impure monohydrochloride.

To prepare the dihydrochloride, the above 6.0 g. was dissolved in 50 ml.of methanol and a large excess of hydrogen chloride was passed in. Thecrystals that separated from the warm solution were filtered, washedwith methanol and then ether. Weight 6.0 g., M.P. 261264 C. (dec.).

Recrystallization from methanol-ether gave pure dihydrochloride, M.P.262-265 C. (dec.).

Analysis for C H N O 2HCl (percent): Calcd.: C, 54.39; H, 6.09; N, 8.46;Cl, 21.41. Found (percent): C, 54.42; H, 6.08; N, 8.38; Cl, 21.25.

EXAMPLE 6 3- (phthalimidomethyl chromone A mixture of 9.7 g. (0.05 mol)of 3-(chloromethyl) chromone, 9.25 g. (0.05 mol) of potassiumphthalimide and 20 ml. of dimethylformamide was heated at 90 C. withstirring for 10 minutes. The mixture was cooled to 50 C. and 100 ml.water was added. The separated solid was filtered, washed well withwater, 2-propanol and then ether. Weight 14.3 g. (93.8%), M.P. 184186 C.

Recrystallization from dimethylformamide-Water gave pure product meltingat 184-186 C.

Analysis for C H NO (percent): Calcd.: C, 70.82; H, 3.63; N, 4.59.Found: C, 70.85; H, 3.63.; N, 4.67.

EXAMPLE 7 3 ,3 l,4-piperazinediyldimethylene) dichromone A quantity of7.0 g. (0.036 mol) of 3-(chloromethyl) chromone was added to a stirredmixture of 3.49 g. (0.018 mol) of piperazine hexahydrate and 100 ml. ofmethylene chloride. Potassium carbonate (20 g.) was added and themixture was warmed on the steam bath. What appeared to be an exothermicreaction soon ensued. The reaction was removed from the heat as refluxwas self-maintained for several minutes. The mixture was stirred for onehour. An additional 300 ml. of methylene chloride was added to helpdissolve the sparingly soluble product. The mixture was filtered and thefilter cake was washed with 200 ml. of methylene chloride. The methylenechloride filtrate was concentrated, the residue was triturated with 20ml. of ether and the mixture was filtered. Weight 6.0 g. (82.8%), M.P.111-113 C.

Recrystallization from chloroform-ether gave pure pale yellow crystalsmelting at 112ll4 C.

Analysis for C H N O (percent): Calcd.: C, 71.62; H, 5.51; N, 6.96.Found: C, 71.60; H, 5.51; N, 6.67.

EXAMPLE 8 3,3 (hydroxyamino dimethylene] dichromone A stirred mixture of6.9 g. (0.1 mol) of hydroxylamine hydrochloride, 10 ml. of water, 150ml. of methylene chloride and 9.73 g. (0.05 mol) of 3-(chloromethyl)chromone was treated with 20 g. potassium carbonate. The deepyellow-orange mixture was maintained at reflux for /2 hour. Themethylene chloride was stripped off and 300 ml. of water was added tothe aqueous carbonate mixture. Te separated solid was filtered, washedwell with water and dried. Weight 5.0 g. (57.3%).

The hydrochloride salt was prepared by treating a suspension of the basein methanol with excess hydrogen chloride M.P. 195-197 C.

Recrystallization from methanol-ether gave pure product, M.P. 196-198 C.The chlorine in the elemental analysis was consistently low.

Analysis for C H NO .HCl (percent): Calcd.: C, 62.26; H, 4.18; N, 3.63;Cl, 9.19. Found: C, 62.38; H, 4.26; N, 3.51; Cl, 7.46.

EXAMPLE 9 3-[ (hydroxymethylamino methyl] chromone Chloroform ml.) wasadded to a solution of 8.36 g. (0.1 mol) of N-methylhydroxylaminehydrochloride, obtained from Aldrich, in 50 ml. of water. Solidpotassium carbonate was added to saturate aqueous layer. At roomtemperature with stirring, a solution of 9.8 g. (0.05 mol) of3-(chloromethyl)chromone in 200 ml. of chloroform was added. Theresulting yellow mixture was stirred for one hour and then heated atreflux for 15 minutes. The organic phase was separated, dried overpotassium carbonate, filtered and concentrated to dryness. The tackyresidue was slurried in 50 ml. of methanol and the mixture was treatedwith excess hydrogen chloride. Most of the solid went into solution. Thesolid was filtered and ether ml.) was added to the filtrate to give 2.6g. (16.7%) crystals melting at l86l89 C.

Recrystallization from methanol-ether gave pure product, M.P. 186189 C.

Analysis for C H NO .HCl (percent): Calcd.: C, 24.67; H, 5.01; N, 5.80.Found: C, 54.76; H, 4.99; N,

EXAMPLE 10 3 ,3 (meth ylamino dimethylene] dichromone Monomethylaminegas was bubbled into a stirred solution of 10.0 g. (0.051 mol) of3-(chloromethyl)chromone in 300 ml. of methylene chloride for 5 minutes.Methylamine hydrochloride separated. After /2 hour at room temperaturethe reaction mixture was warmed on the steam bath and additionalmonomethylamine was bubbled in for three minutes to complete thereaction. Water (50 ml.) and then solid potassium carbonate was added tosaturate the aqueous phase. The organic layer was dried over K COfiltered and concentrated to 20 ml. volume. Upon addition of 100 ml. ofether, 5.0 g. (56.8%) of the crude base was obtained.

The hydrochloride salt was prepared by treating a suspension of the basein methanol with hydrogen chloride gas, M.P. 233 238 C.

Recrystallization from methanol-ether gave pure hydrochloride, M.P. 24925 1 0., existing as a hemimethanolate.

7 Analysis for C H NO HCLlCl-hOH (percent): Calcd.: C, 64.58; H, 5.04;N, 3.50; Cl, 8.87. Found: C, 64.52; H, 5.12; N, 3.40; Cl, 8.47.

EXAMPLE 11 3 I (6-methyl-2-pyridyl) amino] methyljchromone A mixture of7.6 g. (0.04 mol) of 3-(chloromethyl)- chromone and 32.4 g. (0.3 mol) of2-amino-6-methylpyridine was fused at 130 C. for minutes. Water (500ml.) was added to the cooled reaction mixture. The separated oilcrystallized. This was filtered, washed Well with water and dried.Weight 10.7 g. (100%) M.P. 126"- 129 C.

Recrystallization from methanol gave pure base, M.P. 135136 C.

The hydrochloride was prepared by treating a slurry of 5.7 g. of thebase in 60 ml. of methanol with excess hydrogen chloride gas. Most ofthe base dissolved as the white salt separated. Weight 6.2 g., M.P.262265 C.

Recrystallization from methanol-ether gave pure hydrochloride, M.P.262-265 C.

Analysis for C H N O .HCl (percent): Calcd.: C, 63.47; H, 4.99; N, 9.25.Found: C, 63.34; H, 5.15; N, 9.25.

EXAMPLE 12 3-[ (isopropylamino methyl] chromone A solution of 8.3 g.(0.0427 mol) of 3-(chloromethyl)- chromone in 50 m1. of methylenechloride was added over 5 minutes to refluxing isopropylamine (120.2 g.)with stirring. After 15 minutes at reflux, the reaction was stripped ofexcess amine and methylene chloride. Water (50 ml.) was added to theresidue and then solid potassium carbonate was added to saturate. Theseparated orange oil was extracted into a solution of 150 ml. of benzeneand 100 ml. of ether. The extract was dried (K CO charcoaled, filteredand concentrated at atmospheric pressure. The residue was dissolved in50 ml. of ether and treated with hydrogen chloride gas. The separatedtacky yellow salt was dissolved in 100 ml. of hot 2-propanol. Onaddition of 100 ml. ether yellow crystals separated. Weight 5.0 g.(46.3%), M.P. 207- 209 C.

Recrystallization from ethanol-ether gave pure material, IVLP. 209 -21 1C.

Analysis for C H NO .HCl (percent): Calcd.: C, 61.54; H, 6.36; N, 5.52.Found: C, 61.73; H, 6.33; N, 5.34.

EXAMPLE 13 3-(aminomethyl chromone A solution of 4.3 g. (0.014 mol) of3-(phthalimido)- methyl)chromone, 50 ml. of glacial acetic acid and 50ml. of concentrated hydrochloric acid was maintained at reflux for 6hours. Most of the acetic acid and hydrochloric acid were stripped ofiat reduced pressure, water (150 ml.) was added and the phthalic acid wasfiltered. Potassium carbonate was added to the filtrate to neutralizeand then to saturate. The tan, viscous, salted out material wasseparated from the supernatant and heated with 200 ml. of THF to mostlydissolve. Anhydrous potassium carbonate was added to dry the solution.The solution was charcoaled, filtered and treated with hydrogen chloridegas to precipitate a yellow viscous salt. Upon addition of 20 ml. of2-propanol to the separated salt, solid developed. Ether (100 ml.) wasadded and the product was filtered. Weight 0.9 g. (30%), M.P. 187 190 C.

Recrystallization from ethanol-ether gave constant, broad meltingproduct, M.P. 192-195 C. whose elemental analysis was slightly low incarbon.

Analysis for C H NO .HCl (percent):

Calcd.: C,

8 EXAMPLE 14 3,3 (oxydimethyle ne dichromone A quantity of 6.8 g.(0.0386 mol) of 3-hydroxymethyl)- chromone was fused, under nitrogen, at260 C. for 5 minutes. The cooled melt was triturated with 50 ml. ofwater, filtered and washed well with water. The damp filter cake wasdissolved in 30 ml. of hot tetrahydrofuran. The crystals that separatedweighed 0.8 g. (12.4%) and melted at 192 -194 C.

Recrystallization from THE gave pure white product, M.P. 194-196 C.

Analysis for C H O (percent): Calcd.: C, 71.85, H, 4.22. Found C, 72.13,H, 4.24.

EXAMPLE 15 3- methoxymethyl) chromone A solution of 28.88 g. (0.164 mol)of 3-(hydroxymethyl)chromone, 30.0 g. (0.118 mol) of iodine, ml. ofmethanol and 100 ml. of acetone was stirred at room temperature forthree days. The reaction solution was poured into a stirred solution of150 g. of sodium thiosulfate in 600 ml. of water. Sodium chloride wasadded to saturate the solution and the excess methanol and acetone werestripped off. The mixture was extracted with one liter of ether. Theextract was dried over K CO filtered and concentrated. The crude productwas heated with 800 ml. of Skellysolve B" to the boiling point and thehot supernatant was decanted, cooled, filtered (to remove small amountof crude starting material), charcoaled, filtered again and concentratedto give 20.5 g. of tacky, crude product.

Recrystallization from methanol-Water gave 10.3 g. (33%) of good qualityether melting at 7779 C. Further recrystallization from Skellysolve B"gave pure material melting at 77 -79 C.

Analysis for C H O (percent): Calcd.: C, 69.46; H, 5.30. Found: C,69.33; H, 5.19.

EXAMPLE 16 3 (hydroxymethyl chromone acetate A solution of 9.6 g. (0.052mol) of 3-(hydroxymethyl)chromone in 50 ml. of acetic anhydride washeated at 120 C. for 5 minutes. Water (200 ml.) was added and the warmmixture was stirred for one-half hour. The resulting solid was filtered,washed well with water and dried. Weight 6.5 g. (57.6%), M.P. 8486 C.

Recrystallization from ethylacetate-petroleum ether gave pure materialmelting at 85 87 C.

Analysis for C I-1 0 (percent): Calcd.: C, 66.05; H, 4.62. Found: C,65.86; H, 4.48.

EXAMPLE 17 6-bromo-3- (hydroxymethyl) chromone acetate A mixture of 5 g.of 6-bromo-3-(hydroxyrnethyl)chromone and 15 ml. of acetic anhydride wasrefluxed for 15 minutes. The solution was then poured onto 150 ml. ofice water and the solid precipitate was filtered off, washed with coldwater and recrystallized from MeOH, M.P. 146148 C.; yield 4.5 g. (77%);A ma (6) 231 (31,500), 307 (5,650); v,,,,,,, 755 (m.), 840 (In), 1050(111.), 1160 (ms), 1245 (ms), 1600 (m.), 1630 (me), 1725 (ms.)cm.

Analysis for C H BrO (percent): Calcd.: C, 48.51; H, 3.05; Br, 26.89.Found: C, 48.79; H, 2.92; Br. 26.88.

EXAMPLE 18 6-br0mo-3- (hydroxymethyl chromone chloroacetate A solutionof 10 g. of 6-bromo-3-(hydroxymethyl)- chromone and 8.5 g. ofchloracetic anhydride (.1. T. Baker Chem. Co.) in ml. of toluene wasrefiuxed for 4 hours. The solution was then chilled, and the crystallineprecipitate was filtered off, Washed with cold toluene, andrecrystallized from acetone, M.P. 126. 5-128.5 C.; yield wherein R ishalogen, cyano, carboxy, carboxamido, amino, lower alkylamino,phenylamino, lower alkoxy, N- (hydroxy lower alkyl)amino, loweralkanoyloxy and R is hydrogen, halogen or lower alkoxy.

2. A compound according to claim 1 which is 3-(chloromethyl)chromone.

3. A compound according to claim 1 which is 3-chromonylacetonitrile.

O O l I CHzR CH2 R3 10 R I R2 4. A compound according to claim 1 whichis 3-chromonylacetic acid.

5. A compound according to claim 1 which is 3-chromonylacetamide.

6. A compound according to claim 1 which is 3-[(hydroxymthylaminomethyl] chromone.

7. A compound according to claim 1 which is 3-[(isopropylamino methyl]chromone.

8. A compound according to claim 1 which is 3-(amiuomethyl)chromone.

9. A compound according to claim 1 which is 3- (methoxymethyl)chromone.

10. 3-(hydroxymethyl)chromone acetate.

11. 6-bromo-3-(hydroxymethyl)chromone acetate.

12. 6-bromo-3-(hydroxymethyl)chromone chloroacetate.

References Cited UNITED STATES PATENTS 2,769,015 10/ 195 6 Mentzer260345.2

JOHN M. FORD, Primary Examiner U.S. Cl. X.R.

260-3455; 424283; 260268 BC, 326 A, 296 B

